Table 4 displays the number of patients with clinical worsening events in Study 2. Kaplan-Meier estimates and a stratified log-rank test demonstrated that placebo-treated patients were 3 times more likely to experience a clinical worsening event than the sildenafil tablets-treated patients and that sildenafil tablets-treated patients experienced a significant delay in time to clinical worsening versus placebo-treated patients (p = 0.0074). Kaplan-Meier plot of time to clinical worsening is presented in Figure 11.Figure 11.
The primary efficacy endpoint was the change from baseline at week 12 (at least 4 hours after the last dose) in the 6-minute walk distance. The improvement in walk distance was apparent after 4 weeks of treatment and was maintained at week 8 and week 12. Change from Baseline in 6-Minute Walk Distance (meters) at Weeks 4, 8, and 12 in Study 1: Mean (95% Confidence Interval) Figure 10 displays subgroup efficacy analyses in Study 1 for the change from baseline in 6-Minute Walk Distance at Week 12 including baseline walk distance, disease etiology, functional class, gender, age and hemodynamic parameters. Placebo-Corrected Change From Baseline in 6-Minute Walk Distance (meters) at Week 12 by study subpopulation in Study 1: Mean (95% Confidence Interval) Key:PAH = pulmonary arterial hypertension; CTD = connective tissue disease; PH = pulmonary hypertension; PAP = pulmonary arterial pressure; PVRI = pulmonary vascular resistance index; TID = three times daily. Of the 277 treated patients, 259 entered a long-term, uncontrolled extension study.
Without a control group, these data must be interpreted cautiously. Study 2 (Sildenafil tablets co-administered with epoprostenol) A randomized, double-blind, placebo controlled study (Study 2) was conducted in 267 patients with PAH who were taking stable doses of intravenous epoprostenol. Patients were randomized to placebo or sildenafil tablets (in a fixed titration starting from 20 mg, to 40 mg and then 80 mg, three times a day) and all patients continued intravenous epoprostenol therapy. At baseline patients had PPH (80%) or PAH secondary to CTD (20%);WHO functional class I (1%), II (26%), III (67%), or IV (6%); and the mean age was 48 years, 80% were female, and 79% were Caucasian. There was a statistically significant greater increase from baseline in 6-minute walk distance at Week 16 (primary endpoint) for the sildenafil tablets group compared with the placebo group. Kaplan-Meier Plot of Time (in Days) to Clinical Worsening of PAH (in Study 2)Improvements in WHO functional class for PAH were also demonstrated in subjects on sildenafil tablets compared to placebo. More than twice as many sildenafil tablets-treated patients (36%) as the placebo-treated patients (14%) showed an improvement in at least one functional New York Heart Association (NYHA) class for PAH.Study 3 (Sildenafil tablets monotherapy (1 mg, 5 mg, and 20 mg three times a day))A randomized, double-blind, parallel dose study (Study 3) was planned in 219 patients with PAH. This study was prematurely terminated with 129 subjects enrolled. Patients were required to have a mPAP greater than or equal to 25 mmHg and a PCWP less than or equal to 15 mmHg at rest via right heart catheterization within 12 weeks before randomization, and a baseline 6-minute walk test distance greater than or equal to 100 meters and less than or equal to 450 meters (mean 345 meters).
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Patients were randomized to 1 of 3 doses of Sildenafil tablets: 1 mg, 5 mg, and 20 mg, three times a day.At baseline patients had PPH (74%) or secondary PAH (26%); WHO functional class II (57%), III (41%), or IV (2%); the mean age was 44 years; and 67% were female.
The majority of subjects were Asian (67%), and 28% were Caucasian.The primary efficacy endpoint was the change from baseline at Week 12 (at least 4 hours after the last dose) in the 6-minute walk distance. Similar increases in walk distance (mean increase of 38-41 meters) were observed in the 5 and 20 mg dose groups. These increases were significantly better than those observed in the 1 mg dose group (Figure 12).Figure 12. Mean Change from Baseline in Six Minute Walk (meters) by Visit to Week 12 - ITT Population Sildenafil Protocol A1481244Study 4 (Sildenafil Tablets added to bosentan therapy - lack of effect on exercise capacity)A randomized, double-blind, placebo controlled study was conducted in 103 patients with PAH who were on bosentan therapy for a minimum of three months. The PAH patients included those with primary PAH, and PAH associated with CTD. Patients were randomized to placebo or sildenafil (20 mg three times a day) in combination with bosentan (62.5-125 mg twice a day). The primary efficacy endpoint was the change from baseline at Week 12 in 6MWD. The results indicate that there is no significant difference in mean change from baseline on 6MWD observed between sildenafil 20 mg plus bosentan and bosentan alone. Studies of Adults with Pulmonary Arterial Hypertension Study 1 (Sildenafil tablets monotherapy (20 mg, 40 mg, and 80 mg three times a day)) A randomized, double-blind, placebo-controlled study of sildenafil tablets (Study 1) was conducted in 277 patients with PAH (defined as a mean pulmonary artery pressure of greater than or equal to 25 mmHg at rest with a pulmonary capillary wedge pressure less than 15 mmHg).
Patients with left ventricular ejection fraction less than 45% or left ventricular shortening fraction less than 0.2 also were not studied.
PATIENT COUNSELING INFORMATION See FDA-approved patient labeling ( Patient Information).Inform patients of contraindication of sildenafil tablets with regular and/or intermittent use of organic nitrates.Inform patients that sildenafil tablets is also marketed as VIAGRA for erectile dysfunction. Advise patients taking sildenafil tablets not to take VIAGRA or other PDE-5 inhibitors.Advise patients to seek immediate medical attention for a sudden loss of vision in one or both eyes while taking sildenafil tablets. Such an event may be a sign of NAION.Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking sildenafil tablets. These events may be accompanied by tinnitus and dizziness. See FDA-approved patient labeling ( Patient Information). Patients were randomized to receive placebo (n=70) or sildenafil tablets, 20 mg (n = 69), 40 mg (n = 67) or 80 mg (n = 71) three times a day for a period of 12 weeks. The study population consisted of 25% men and 75% women with a mean age of 49 years (range: 18–81 years) and baseline 6-minute walk distance between 100 and 450 meters (mean 343). The primary efficacy endpoint was the change from baseline at week 12 (at least 4 hours after the last dose) in the 6-minute walk distance. The improvement in walk distance was apparent after 4 weeks of treatment and was maintained at week 8 and week 12. Change from Baseline in 6-Minute Walk Distance (meters) at Weeks 4, 8, and 12 in Study 1: Mean (95% Confidence Interval) Figure 10 displays subgroup efficacy analyses in Study 1 for the change from baseline in 6-Minute Walk Distance at Week 12 including baseline walk distance, disease etiology, functional class, gender, age and hemodynamic parameters. Placebo-Corrected Change From Baseline in 6-Minute Walk Distance (meters) at Week 12 by study subpopulation in Study 1: Mean (95% Confidence Interval) Key:PAH = pulmonary arterial hypertension; CTD = connective tissue disease; PH = pulmonary hypertension; PAP = pulmonary arterial pressure; PVRI = pulmonary vascular resistance index; TID = three times daily.
Inform patients of contraindication of sildenafil tablets with regular and/or intermittent use of organic nitrates. Inform patients that sildenafil tablets is also marketed as VIAGRA for erectile dysfunction. Advise patients taking sildenafil tablets not to take VIAGRA or other PDE-5 inhibitors. Of the 277 treated patients, 259 entered a long-term, uncontrolled extension study. Without a control group, these data must be interpreted cautiously. Study 2 (Sildenafil tablets co-administered with epoprostenol) A randomized, double-blind, placebo controlled study (Study 2) was conducted in 267 patients with PAH who were taking stable doses of intravenous epoprostenol. Patients were randomized to placebo or sildenafil tablets (in a fixed titration starting from 20 mg, to 40 mg and then 80 mg, three times a day) and all patients continued intravenous epoprostenol therapy. At baseline patients had PPH (80%) or PAH secondary to CTD (20%);WHO functional class I (1%), II (26%), III (67%), or IV (6%); and the mean age was 48 years, 80% were female, and 79% were Caucasian. There was a statistically significant greater increase from baseline in 6-minute walk distance at Week 16 (primary endpoint) for the sildenafil tablets group compared with the placebo group. The mean change from baseline at Week 16 (last observation carried forward) was 30 meters for sildenafil 100g the sildenafil tablets group compared with 4 meters for the placebo group giving an adjusted treatment difference of 26 meters (95% CI: 10.8, 41.2) (p = 0.0009). Patients on sildenafil tablets achieved a statistically significant reduction in mPAP compared to those on placebo.
The mean change from baseline at Week 16 (last observation carried forward) was 30 meters for sildenafil 100g the sildenafil tablets group compared with 4 meters for the placebo group giving an adjusted treatment difference of 26 meters (95% CI: 10.8, 41.2) (p = 0.0009). Patients on sildenafil tablets achieved a statistically significant reduction in mPAP compared to those on placebo. A mean placebo-corrected treatment effect of -3.9 mmHg was observed in favor of sildenafil tablets (95% CI: -5.7, -2.1) (p = 0.00003). Time to clinical worsening of PAH was defined as the time from randomization to the first occurrence of a clinical worsening event (death, lung transplantation, initiation of bosentan therapy, or clinical deterioration requiring a change in epoprostenol therapy). Kaplan-Meier plot of time to clinical worsening is presented in Figure 11.
Kaplan-Meier Plot of Time (in Days) to Clinical Worsening of PAH (in Study 2) Improvements in WHO functional class for PAH were also demonstrated in subjects on sildenafil tablets compared to placebo. More than twice as many sildenafil tablets-treated patients (36%) as the placebo-treated patients (14%) showed an improvement in at least one functional New York Heart Association (NYHA) class for PAH. Study 3 (Sildenafil tablets monotherapy (1 mg, 5 mg, and 20 mg three times a day)) A randomized, double-blind, parallel dose study (Study 3) was planned in 219 patients with PAH. Patients were randomized to 1 of 3 doses of Sildenafil tablets: 1 mg, 5 mg, and 20 mg, three times a day. At baseline patients had PPH (74%) or secondary PAH (26%); WHO functional class II (57%), III (41%), or IV (2%); the mean age was 44 years; and 67% were female. A mean placebo-corrected treatment effect of -3.9 mmHg was observed in favor of sildenafil tablets (95% CI: -5.7, -2.1) (p = 0.00003).
Table 4 displays the number of patients with clinical worsening events in Study 2. Kaplan-Meier estimates and a stratified log-rank test demonstrated that placebo-treated patients were 3 times more likely to experience a clinical worsening event than the sildenafil tablets-treated patients and that sildenafil tablets-treated patients experienced a significant delay in time to clinical worsening versus placebo-treated patients (p = 0.0074). Kaplan-Meier plot of time to clinical worsening is presented in Figure 11.Figure 11. Kaplan-Meier Plot of Time (in Days) to Clinical Worsening of PAH (in Study 2)Improvements in WHO functional class for PAH were also demonstrated in subjects on sildenafil tablets compared to placebo. More than twice as many sildenafil tablets-treated patients (36%) as the placebo-treated patients (14%) showed an improvement in at least one functional New York Heart Association (NYHA) class for PAH.Study 3 (Sildenafil tablets monotherapy (1 mg, 5 mg, and 20 mg three times a day))A randomized, double-blind, parallel dose study (Study 3) was planned in 219 patients with PAH.
This study was prematurely terminated with 129 subjects enrolled. Patients were required to have a mPAP greater than or equal to 25 mmHg and a PCWP less than or equal to 15 mmHg at rest via right heart catheterization within 12 weeks before randomization, and a baseline 6-minute walk test distance greater than or equal to 100 meters and less than or equal to 450 meters (mean 345 meters). Patients were randomized to 1 of 3 doses of Sildenafil tablets: 1 mg, 5 mg, and 20 mg, three times a day.At baseline patients had PPH (74%) or secondary PAH (26%); WHO functional class II (57%), III (41%), or IV (2%); the mean age was 44 years; and 67% were female. The majority of subjects were Asian (67%), and 28% were Caucasian.The primary efficacy endpoint was the change from baseline at Week 12 (at least 4 hours after the last dose) in the 6-minute walk distance. Similar increases in walk distance (mean increase of 38-41 meters) were observed in the 5 and 20 mg dose groups. Time to clinical worsening of PAH was defined as the time from randomization to the first occurrence of a clinical worsening event (death, lung transplantation, initiation of bosentan therapy, or clinical deterioration requiring a change in epoprostenol therapy).
The majority of subjects were Asian (67%), and 28% were Caucasian. These increases were significantly better than those observed in the 1 mg dose group (Figure 12). Mean Change from Baseline in Six Minute Walk (meters) by Visit to Week 12 - ITT Population Sildenafil Protocol A1481244 Study 4 (Sildenafil Tablets added to bosentan therapy - lack of effect on exercise capacity) A randomized, double-blind, placebo controlled study was conducted in 103 patients with PAH who were on bosentan therapy for a minimum of three months. HOW SUPPLIED/STORAGE AND HANDLING Sildenafil Tablets, USP 20 mg are supplied as white round, biconvex film coated tablets debossed with "R" on one side and "20" on the other side, containing sildenafil citrate equivalent to the nominally indicated amount of sildenafil as follows:Recommended Storage for Sildenafil Tablets, USP: Store at 20°C-25°C (68°F-77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature]. Sildenafil Tablets, USP 20 mg are supplied as white round, biconvex film coated tablets debossed with "R" on one side and "20" on the other side, containing sildenafil citrate equivalent to the nominally indicated amount of sildenafil as follows: Recommended Storage for Sildenafil Tablets, USP: Store at 20°C-25°C (68°F-77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature]. Kaplan-Meier plot of time to clinical worsening is presented in Figure 11. Kaplan-Meier Plot of Time (in Days) to Clinical Worsening of PAH (in Study 2) Improvements in WHO functional class for PAH were also demonstrated in subjects on sildenafil tablets compared to placebo. More than twice as many sildenafil tablets-treated patients (36%) as the placebo-treated patients (14%) showed an improvement in at least one functional New York Heart Association (NYHA) class for PAH.
These increases were significantly better than those observed in the 1 mg dose group (Figure 12).Figure 12. Mean Change from Baseline in Six Minute Walk (meters) by Visit to Week 12 - ITT Population Sildenafil Protocol A1481244Study 4 (Sildenafil Tablets added to bosentan therapy - lack of effect on exercise capacity)A randomized, double-blind, placebo controlled study was conducted in 103 patients with PAH who were on bosentan therapy for a minimum of three months. The PAH patients included those with primary PAH, and PAH associated with CTD. Patients were randomized to placebo or sildenafil (20 mg three times a day) in combination with bosentan (62.5-125 mg twice a day). The primary efficacy endpoint was the change from baseline at Week 12 in 6MWD.
The results indicate that there is no significant difference in mean change from baseline on 6MWD observed between sildenafil 20 mg plus bosentan and bosentan alone. Studies of Adults with Pulmonary Arterial Hypertension Study 1 (Sildenafil tablets monotherapy (20 mg, 40 mg, and 80 mg three times a day)) A randomized, double-blind, placebo-controlled study of sildenafil tablets (Study 1) was conducted in 277 patients with PAH (defined as a mean pulmonary artery pressure of greater than or equal to 25 mmHg at rest with a pulmonary capillary wedge pressure less than 15 mmHg). Patients with left ventricular ejection fraction less than 45% or left ventricular shortening fraction less than 0.2 also were not studied. Patients were randomized to receive placebo (n=70) or sildenafil tablets, 20 mg (n = 69), 40 mg (n = 67) or 80 mg (n = 71) three times a day for a period of 12 weeks. The study population consisted of 25% men and 75% women with a mean age of 49 years (range: 18–81 years) and baseline 6-minute walk distance between 100 and 450 meters (mean 343). Study 3 (Sildenafil tablets monotherapy (1 mg, 5 mg, and 20 mg three times a day)) A randomized, double-blind, parallel dose study (Study 3) was planned in 219 patients with PAH.
Patients were randomized to 1 of 3 doses of Sildenafil tablets: 1 mg, 5 mg, and 20 mg, three times a day. At baseline patients had PPH (74%) or secondary PAH (26%); WHO functional class II (57%), III (41%), or IV (2%); the mean age was 44 years; and 67% were female.
| Country | Approval Status | Maximum Allowed Dose | Remarks |
|---|---|---|---|
| United States | Approved for ED and pulmonary hypertension | 120 mg | Prescription-only, controlled use |
| European Union | Approved for ED, off-label for other uses | 120 mg | Stringent prescribing regulations |
| Canada | Approved, similar to US | 120 mg | Must be prescribed by healthcare provider |
| Australia | Approved with restrictions | 120 mg | Medical supervision required |
| India | Available, OTC in some regions | 120 mg | Use under medical guidance recommended |
The majority of subjects were Asian (67%), and 28% were Caucasian. These increases were significantly better than those observed in the 1 mg dose group (Figure 12). Mean Change from Baseline in Six Minute Walk (meters) by Visit to Week 12 - ITT Population Sildenafil Protocol A1481244 Study 4 (Sildenafil Tablets added to bosentan therapy - lack of effect on exercise capacity) A randomized, double-blind, placebo controlled study was conducted in 103 patients with PAH who were on bosentan therapy for a minimum of three months. HOW SUPPLIED/STORAGE AND HANDLING Sildenafil Tablets, USP 20 mg are supplied as white round, biconvex film coated tablets debossed with "R" on one side and "20" on the other side, containing sildenafil citrate equivalent to the nominally indicated amount of sildenafil as follows:Recommended Storage for Sildenafil Tablets, USP: Store at 20°C-25°C (68°F-77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature]. Sildenafil Tablets, USP 20 mg are supplied as white round, biconvex film coated tablets debossed with "R" on one side and "20" on the other side, containing sildenafil citrate equivalent to the nominally indicated amount of sildenafil as follows: Recommended Storage for Sildenafil Tablets, USP: Store at 20°C-25°C (68°F-77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature]. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling ( Patient Information).Inform patients of contraindication of sildenafil tablets with regular and/or intermittent use of organic nitrates.Inform patients that sildenafil tablets is also marketed as VIAGRA for erectile dysfunction. Advise patients taking sildenafil tablets not to take VIAGRA or other PDE-5 inhibitors.Advise patients to seek immediate medical attention for a sudden loss of vision in one or both eyes while taking sildenafil tablets. Such an event may be a sign of NAION.Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking sildenafil tablets. These events may be accompanied by tinnitus and dizziness. See FDA-approved patient labeling ( Patient Information). Inform patients of contraindication of sildenafil tablets with regular and/or intermittent use of organic nitrates. Inform patients that sildenafil tablets is also marketed as VIAGRA for erectile dysfunction. Advise patients taking sildenafil tablets not to take VIAGRA or other PDE-5 inhibitors.